This invention relates to novel compositions and kits comprising (a) a bretylium cation, and (b) a facilitating anion and/or a xcex2-receptor blocker. This invention also relates to the use of such compositions and kits to prevent and/or treat cardiovascular conditions.
Bretylium tosylate 1 (also known as o-bromobenzylethyldimethylammonium p-toluenesulfonate) has the structure: 
It is a known Class III antiarrhythmic agent and an adrenergic blocking agent. The bretylium cation of this compound is reported to directly modify the electrical properties of the myocardium. It also is reported to depress adrenergic neural transmission by blocking neuronal norepinephrine release and re-uptake. Bretylium tosylate consequently has been used worldwide to suppress life-threatening ventricular tachyarrhythmias, such as ventricular tachycardia and fibrillation. Bacaner (in U.S. Reissue Pat. No. 29,618) discloses suppressing cardiac ventricular fibrillation and cardiac arrhythmias generally by administering bretylium tosylate. Similarly, Bacaner (in U.S. Pat. No. 3,911,125) discloses treating angina pectoris, treating coronary insufficiency, and preventing myocardial infarction by administering bretylium tosylate.
Unformulated bretylium tosylate exhibits poor and unpredictable absorption when orally ingested. Thus, oral administration of bretylium tosylate alone is generally unsuitable for treating heart conditions and has not been approved by the FDA. Accordingly, bretylium tosylate is instead usually administered parenterally in the form of an injectable solution. This mode of administration, however, is both inconvenient and painful, particularly for chronic administration.
Administration of bretylium tosylate also can result in severely reduced ambulation in a recipient due to a sharp drop in blood pressure on assuming the upright position, resulting in dizziness and loss of consciousness. The severity of this side-effect, however, can be reduced (and the therapeutic effects of the bretylium cation can be enhanced) by administering a tricyclic anti-depressant agent (e.g., protriptyline, mazindol, amitriptyline, nortriptyline, or desipramine) with the bretylium tosylate, as disclosed by Bacaner in U.S. Pat. No. 5,036,106.
A number of studies on the bioavailability of bretylium tosylate have been described in the literature. Most these studies, however, have primarily focused on parenteral, rectal, and other non-ingested compositions comprising bretylium tosylate. Most also involve the administration of bretylium tosylate compositions under alkaline conditions.
Neubert et al. (in Ion Pair Approach of Bretylium, Pharm. Ind. 54, Nr. 4 (1992)) disclose a series of experiments in which bretylium tosylate was studied in the presence of saccharin, dodecylsulfate, or hexylsalicylate anions. The partition coefficients for the bretylium ion were measured in the presence of these anions using an alkaline (pH=7.2) n-octanol/buffer system and using an alkaline (pH=7.2) absorption model system employing an artificial lipid membrane. Bretylium absorption in vivo was also measured in rabbits receiving the bretylium tosylate in combination with these anions by i.v. injection (an i.v. injection of bretylium tosylate in Sorensen phosphate buffer (pH=7.2), together with an i.v. injection of hexylsalicylic acid in ethanol/Sorensen phosphate buffer (pH=7.2)) or rectal administration.
Neubert et al. (in Influence of Lipophilic Counter Ions on the Transport of Ionizable Hydrophilic Drugs, J. Pharm. Pharmacol. 1991, 43: 204-206) disclose a series of experiments on the influence of the counterions hydroxynaphthoate, naphthylsulphonate, adamantoate, desoxycholate, dehydrocholate, octanoate, decanoate, dodecanoate, hexadecanoate, and hexylsalicylate on the transport of bretylium using an alkaline (pH=7.2) absorption model system. It was reported that the use of hydroxynaphthoate, adamantoate, desoxycholate, or dehydrocholate counterions resulted in minimal or no increase in bretylium transport across the membrane. No therapeutic or electrophysiologic action is disclosed.
Neubert et al. (in Drug Permeation Through Artificial Lipoid Membranes, Pharmazie 42 (1987), H. 5) evaluated the effect of alkylated derivatives of salicylic acid, particularly hexylsalicylic acid, on the partition and transport of ionized basic drugs including bretylium tosylate using lipophilic membranes in alkaline (pH=7.2) lipoid membrane models.
Hartl et al. (in Influence of the Ion-Pair-Formation of Bretylium and Hexylsalicylic Acid on Their Influence on Blood Plasma Levels in Dogs, Pharmazie 45 (1990), H. 4) report an improvement in biological bretylium levels in dog plasma when a bretylium-tosylate/hexylsalicylic-acid combination was administered to dogs by i.v. injection (an i.v. injection of bretylium tosylate in Sorensen phosphate buffer (pH=7.2), together with an i.v. injection of hexylsalicylic acid in ethanol/Sorensen phosphate buffer (pH=7.2)). Hartl et al., however, do not discuss how to improve the bretylium level in the myocardium of the heart or the therapeutic effects of doing so.
Neubert et al. (in Influence of the Ion-Pair-Formation on the Pharmacokinetic Properties of Drugs (Part 4), Pharmazie 43 (1988), H. 12) report a series of experiments to determine the pharmocokinetic parameters of bretylium tosylate administered in combination with hexylsalicylic acid in rabbits by i.v. injection or rectally. No therapeutic or electrophysiologic action is disclosed.
Amlacher et al. (in Influence of Ion-Pair Formation on the Pharmacokinetic Properties of Drugs, J. Pharm. Pharmacol. 1991, 43: 794-797) disclose a series of experiments to measure the partition coefficients for the bretylium ion in the presence of salicylic acid using an alkaline (pH=7.2) n-octanol/buffer system. Bretylium absorption in vivo was also measured in rabbits receiving an i.v. injection of bretylium tosylate in Sorensen phosphate buffer (pH=7.2), together with an i.v. injection of hexylsalicylic acid in ethanol/Sorensen phosphate buffer (pH 7.2).
Neubert et al. (in Influence of the Ion-Pair-Formation on the Pharmacokinetic Properties of Drugs (Part 5), Pharmazie 44 (1989), H. 9) disclose a series of experiments on the effect of ion-pair formation on the elimination of bretylium and hexylsalicylic acid in rats. In these experiments, the rats received an i.v. injection of bretylium tosylate in Sorensen phosphate buffer (pH=7.2), together with an i.v. injection of hexylsalicylic acid in ethanol/Sorensen phosphate buffer (pH=7.2) and, in some instances, an oral dose of cholestyramine. Neubert et al. concluded that the pharmacokinetic parameters of bretylium were not influenced by hexylsalicylic acid.
Cho (in WO 87/05505) discloses compositions comprising particles consisting essentially of a solid emulsifying agent and a surfactant, a biologically active proteinaceous material bound to the surface of the particles, and a lipid coating surrounding such particles. While Cho is primarily directed to pharmaceutical compositions comprising insulin, he does state generally that other pharmaceutical agents, such as bretylium tosylate, could be employed. Additional ingredients in the composition are described to include, among others, sodium lauryl sulfate (as a surfactant), sodium bicarbonate, and citric acid.
Stanley et al. (in U.S. Pat. Nos. 5,288,497 and 5,288,498) disclose a dissolvable or non-dissolvable drug containing matrix form for administering a drug for absorption through the mucosal tissues of the mouth, pharynx, and esophagus. Stanley et al. identify a large group of active drugs that can be administered buccally in accordance with the invention. These references further disclose a variety of additional ingredients that can be included in the matrix including, among others, sodium lauryl sulfate and sodium dodecyl sulfate (as xe2x80x9cpermeation enhancersxe2x80x9d) and buffering systems (to adjust salival pH). Although the Stanley references list bretylium tosylate as one of the drugs that can be administered in this manner, bretylium tosylate is very bitter and too unpalatable for human consumption by this mode of administration.
Finally, Bacaner et al. (in xe2x80x9cSynergistic Action of Bretylium With Low Doses Of Propranolol Renders The Canine Heart Virtually Invulnerable To Sustained Ventricular Fibrillationxe2x80x9d, Circulation, Supp. IV, page 111 (1987)) disclose a synergistic enhancement in the onset and magnitude of the antifibrillatory action caused by bretylium tosylate when a small, non-xcex2-blocking dosage of propranolol is added to a bretylium tosylate bolus injected into dogs.
This invention provides, in part, novel pharmaceutical compositions and kits which may be administered to prevent and/or treat medical conditions related to the cardiovascular system. These compositions and kits have been found to be particularly suitable for oral administration, although they also have been found to be generally useful when administered parenterally.
Briefly, therefore, this invention is directed to pharmaceutical compositions and kits useful for preventing and/or treating a cardiovascular condition. As defined herein, the term xe2x80x9ccompositionxe2x80x9d refers to a single compound or a mixture of compounds. A xe2x80x9ckit,xe2x80x9d in contrast, refers collectively to therapeutic ingredients which are in the form of at least two separate, discrete sources that are independently administered (whether jointly or at different times).
Some embodiments of this invention, for example, are directed to a pharmaceutical composition comprising a bretylium cation and a facilitating anion, wherein (a) the facilitating anion is less hydrophilic than a tosylate anion, (b) the pharmaceutical composition is suitable for oral ingestion, (c) the pharmaceutical composition is capable of forming a mixture comprising both the bretylium cation and the facilitating anion within the gastrointestinal tract of a subject upon ingestion by the subject, and (d) the bretylium cation and the facilitating anion together are present in the pharmaceutical composition in a therapeutically effective amount (i.e., the combination of the bretylium cation and the facilitating anion is present in the pharmaceutical composition in a therapeutically effective amount). In one embodiment of this invention, the pharmaceutical composition is identifiable by the following: when the pharmaceutical composition is orally administered to a human, the area under a plot of the bretylium cation concentration in the human""s blood versus time over about 30 minutes following the oral administration is greater than the area under a plot of the bretylium cation concentration in the blood versus time over about 30 minutes following an oral administration of bretylium tosylate in an amount which supplies an equivalent amount of the bretylium cation as is supplied by the oral administration of the pharmaceutical composition. In an even more preferred embodiment, the pharmaceutical composition is identifiable by the following: when the pharmaceutical composition is orally administered to a human, the area under a plot of the bretylium cation concentration in the human""s myocardium versus time over about 30 minutes following the oral administration is greater than the area under a plot of the bretylium cation concentration in the myocardium versus time over about 30 minutes following an oral administration of bretylium tosylate in an amount which supplies an equivalent amount of the bretylium cation as is supplied by the oral administration of the pharmaceutical composition.
Other embodiments of this invention are directed to a pharmaceutical kit useful for preventing and/or treating a cardiovascular condition comprising a source of a bretylium cation and a source of a facilitating anion, wherein: (a) the facilitating anion is less hydrophilic than a tosylate anion, (b) the source of the bretylium cation and the source of the facilitating anion are both suitable for oral ingestion, (c) the source of the bretylium cation and the source of the facilitating anion are capable of forming a mixture comprising both the bretylium cation and the facilitating anion within the gastrointestinal tract of a subject upon ingestion by the subject of the source of the bretylium cation and the source of the facilitating anion, and (d) the bretylium cation and the facilitating anion are present in the kit in a therapeutically effective amount (i.e., the bretylium cation and the facilitating anion are present in the kit in amounts such that their combination is therapeutically effective after both are administered). In one embodiment of this invention, the kit is identifiable by the following: when the source of the bretylium cation and the source of the facilitating anion are orally administered to a human, the area under a plot of the bretylium cation concentration in the human""s blood versus time over about 30 minutes following the oral administration is greater than the area under a plot of the bretylium cation concentration in the blood versus time over about 30 minutes following an oral administration of bretylium tosylate in an amount which supplies an equivalent amount of the bretylium cation as is supplied by the oral administration of the source of the bretylium cation together with the source of the facilitating anion. In an even more preferred embodiment, the kit is identifiable by the following: when the source of the bretylium cation and the source of the facilitating anion are orally administered to a human, the area under a plot of the bretylium cation concentration in the human""s myocardium versus time over about 30 minutes following the oral administration is greater than the area under a plot of the bretylium cation concentration in the myocardium versus time over about 30 minutes following an oral administration of bretylium tosylate in an amount which supplies an equivalent amount of the bretylium cation as is supplied by the oral administration of the source of the bretylium cation together with the source of the facilitating anion.
Other embodiments of this invention are directed to a pharmaceutical composition comprising a bretylium cation and a facilitating anion (or a pharmaceutical kit comprising a source of a bretylium cation and a source of a facilitating anion). In one such embodiment, the facilitating anion in this embodiment comprises an anion selected from the group consisting of:
R2SO3xe2x88x92, 
a pseudo-icosahedral carboranes anion (CB11H12), and
a substituted pseudo-icosahedral carborane anion.
Here, R2, R3, R4, R6, R7, R8, R9, R10, R11, R12, R13, R14, R15, R16, and the substituent(s) of the substituted pseudo-icosahedral carborane anion are independently hydrocarbyl or substituted hydrocarbyl; and the bretylium cation and the facilitating anion together are present in the pharmaceutical composition in a therapeutically effective amount (or, in the case of a kit, the bretylium cation and the facilitating anion are present in the kit in amounts such that their combination is therapeutically effective after both are administered).
In another embodiment directed to a pharmaceutical composition comprising a bretylium cation and a facilitating anion (or a pharmaceutical kit comprising a source of a bretylium cation and a source of a facilitating anion), the facilitating anion has the formula R1OSO3xe2x88x92wherein R1 is hydrocarbyl or substituted hydrocarbyl. The pharmaceutical composition (or kit) also comprises an anti-hypotensive agent and/or a xcex2-receptor blocker. Here, the bretylium cation, the facilitating anion, and the anti-hypotensive agent and/or the xcex2-receptor blocker together are present in the pharmaceutical composition in a therapeutically effective amount (or, in the case of a kit, the bretylium cation, the facilitating anion, and the anti-hypotensive agent and/or the xcex2-receptor blocker are present in the kit in amounts such that their combination is therapeutically effective after they are administered).
In another embodiment directed to a pharmaceutical composition comprising a bretylium cation and a facilitating anion (or a pharmaceutical kit comprising a source of a bretylium cation and a source of a facilitating anion), the facilitating anion has the formula: 
wherein R5 is hydrocarbyl or substituted hydrocarbyl. The pharmaceutical composition (or kit) also comprises a neutralizing agent, an anti-hypotensive agent, and/or a xcex2-receptor blocker. The bretylium cation; the neutralizing agent, the anti-hypotensive agent, and/or the xcex2-receptor blocker; and the facilitating anion together are present in the pharmaceutical composition in a therapeutically effective amount (or, in the case of a kit, the bretylium cation; the neutralizing agent, the anti-hypotensive agent, and/or the xcex2-receptor blocker; and the facilitating anion are present in the kit in amounts such that their combination is therapeutically effective after they are administered).
In another embodiment directed to a pharmaceutical composition comprising a bretylium cation and a facilitating anion (or a pharmaceutical kit comprising a source of a bretylium cation and a source of a facilitating anion), the facilitating anion has the formula: 
wherein R17 is hydrocarbyl or substituted hydrocarbyl; and R18 is hydrogen, hydrocarbyl, or substituted hydrocarbyl. Here, the bretylium cation and the facilitating anion together are present in the pharmaceutical composition in a therapeutically effective amount (or, in the case of a kit, the bretylium cation and the facilitating anion are present in the kit in amounts such that their combination is therapeutically effective after both are administered).
Other embodiments of this invention are directed to a pharmaceutical composition comprising a bretylium cation and a xcex2-receptor blocker (or a pharmaceutical kit comprising a source of a bretylium cation and a source of a xcex2-receptor blocker). In these embodiments, the xcex2-receptor blocker preferably is selected from the group consisting of atenolol, esmolol, metoprolol, labetalol, talinolol, timolol, acebutolol, dichloroisoproterenol, pronethalol, sotalol, oxprenolol, alprenolol, practolol, nadolol, pindolol, penbutolol, and carvedilol. Here, the bretylium cation and the xcex2-receptor blocker together are present in the pharmaceutical composition in a therapeutically effective amount (or, in the case of a kit, the bretylium cation and the xcex2-receptor blocker are present in the kit in amounts such that their combination is therapeutically effective after both are administered).
This invention is also directed to safe methods for treating and/or preventing cardiovascular conditions by administering the above-summarized compositions and kits to a subject (particularly mammal subjects) in need thereof.
Other objects and features of this invention will be in part apparent and in part pointed out hereinafter.